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Originally published online as doi:10.1189/jlb.1103538 on February 3, 2004

Published online before print February 3, 2004
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(Journal of Leukocyte Biology. 2004;76:36-41.)
© 2004 by Society for Leukocyte Biology

Estrogen replacement, aging, and cell-mediated immunity after injury

Elizabeth J. Kovacs*,{dagger},{ddagger},§,1, Timothy P. Plackett*,{ddagger},2 and Pamela L. Witte*,{dagger}

* Department of Cell Biology, Neurobiology, and Anatomy,
{dagger} Immunology and Aging Program,
{ddagger} Burn and Shock Trauma Institute,
§ Department of Surgery, Loyola University Chicago, Maywood, Illinois

1Correspondence: Department of Cell Biology, Neurobiology, and Anatomy, Department of Surgery, Loyola University Chicago, Stritch School of Medicine, Building 110, Room 4237, 2160 South First Avenue, Maywood, IL 60513. E-mail: ekovacs{at}lumc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We recently demonstrated that aged mice are less likely to survive following traumatic injury and are more immunosuppressed than young mice who sustain comparable injuries. Immunosuppression in severely injured patients and in rodent models of burn injury is associated with a marked elevation in proinflammatory cytokines, including interleukin-6 (IL-6). We reported that after sustaining a moderate-size scald injury, aged mice have higher circulating levels of IL-6 than young, injured mice. As proestrus levels of estrogen have been reported to boost immune responses and attenuate IL-6 production, in the present study, we went on to determine if estrogen replacement in aged female mice restored cellular immunity and proinflammatory cytokine production. After injury, in placebo-treated, aged animals, there was a >75% suppression in the delayed-type hypersensitivity response relative to placebo-treated, sham-injured, aged mice (P<0.05). In contrast, estrogen supplementation before injury yielded a partial recovery in this response, such that the mice were suppressed by only 40% relative to sham-injured, aged mice (P<0.05). There was a fourfold increase in the circulating level of IL-6 in burn-injured, aged mice who received placebo hormone replacement relative to sham-injured mice given placebo (P<0.05). This level of cytokine was lowered by nearly 50% in aged, estrogen-treated mice. Most remarkably, estrogen replacement improved survival from 42% (in the absence of estrogen) to 70% in aged, burn-injured mice. Further investigation will be needed to determine if age- and gender-specific therapies are needed for the treatment of all trauma patients.

Key Words: immunosenescence • interleukin-6 • innate immunity • burn


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Elderly subjects who suffer a burn trauma exhibit greater mortality than young-adult burn victims [1 2 3 4 5 ]. A moderate-size burn injury covering 20% of the total body surface area (TBSA) is associated with a mortality of only 20% in healthy, young-adult patients, and a burn of the same size in elderly patients results in a mortality of 75% [3 ]. It is clear that many factors may contribute to the increased lethality of moderate-size burns in the elderly population, including the well-documented reduction in immune function associated with the natural aging process [6 7 8 ]. The functional integrity of immune responses after injury is of paramount importance, as it is well known that regardless of age, burn patients usually succumb to secondary infectious complications rather than their primary injury [9 , 10 ].

Evidence suggests that along with impaired lymphocyte functions [11 12 13 14 ], burn injury affects macrophage production of proinflammatory cytokines and arachidonic acid metabolites [15 16 17 18 19 ], which could in turn influence lymphocyte responses. Several studies have reported elevated levels of macrophage-derived mediators, including interleukin-1 (IL-1), IL-6, tumor necrosis factor {alpha} (TNF-{alpha}), and prostaglandin E2 (PGE2), in the sera and tissues of burned animals and patients [20 21 22 23 24 25 ].

The level of production of these proinflammatory mediators in the absence of injury is minimal and increases markedly after injury or trauma. In contrast, the normal aging process is associated with increased levels of these cytokines [26 ], most notably IL-6 [27 28 29 30 ]. Thus, it is likely that aged individuals are predisposed to a poor outcome after injury by virtue of an overproduction of mediators such as IL-6 and their weakened immune system.

The well-documented, post-menopausal decline in the levels of gonadal steroid hormones, including estrogen, could be responsible for the observed elevation in proinflammatory cytokines seen in the elderly. Physiological levels of estradiol observed during the reproductive years boost immune responsiveness in young adults [31 ], and hormone replacement therapy (HRT) in postmenopausal women appears to improve many immune parameters when compared with controls [32 , 33 ]. Although mechanisms responsible for this beneficial effect of physiologic levels of estrogen have not been completely elucidated, studies suggest that HRT lowers the production of proinflammatory cytokines such as IL-6 [34 ]. In the present study, we elected to examine cellular immune responses in aged versus young mice following burn injury and determine whether estrogen replacement in aged mice could lower aberrant production of proinflammatory cytokines and restore immunity after injury.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Induction of burn injury
Young (3–4 months) and aged (18–22 months), female, BALB/c mice from the National Institute on Aging’s breeding colonies at Charles River (Portage, MI) and Harlan Sprague Dawley (Indianapolis, IN) were maintained on a 12-h light/dark cycle with food and water available ad libitum. Mice were subjected to a 15% TBSA dorsal scald or sham injury as described previously [35 ]. In brief, after induction of anesthesia [nembutal 40 mg/kg, intraperitoneally (i.p.)], clippers were used to remove the hair from the dorsum of each animal. Anesthetized mice receiving scald injuries were placed on their dorsum in a plastic template that exposed 15% TBSA and immersed in a 100°C water bath for 8 s. Following burn injury, mice were immediately dried off to prevent any further scalding. Sham-injured animals were anesthetized, shaved, held in a plastic template, and placed into a room-temperature water bath for the same time period. Burned and sham-injured animals were resuscitated with 1.0 ml 0.9% normal saline (i.p.) and allowed to recover under a heat lamp. After recovery from anesthesia, mice were returned to their cages and maintained under barrier conditions in the animal facility. The animal studies described herein were performed in strict accordance with the guidelines set forth by the Loyola University Chicago Institutional Animal Care and Use Committee (Maywood, IL). At the time of sacrifice, all mice were dissected and the organs screened for visible tumors and/or gross abnormalities. Animals with visible tumors or abnormalities were excluded from these studies.

Analyses of cell-mediated, immune responses
Delayed-type hypersensitivity (DTH) responses were measured as described previously [35 ]. In brief, 5 days before injury, all groups of experimental mice were sensitized to hapten 2,4-dinitrofluorobenzene (DNFB; Sigma Chemical Co., St. Louis, MO) by applying 20 µl of a 0.5% solution in acetone:olive oil (4:1) directly to the shaved skin of the abdomen. Immediately after burn or sham injuries, ear-thickness measurements were made with engineering calipers, and then an eliciting dose (20 µl 0.2% DNFB) was applied to the pinna of the right ear. Ear-thickness measurements were made 24 h after elicitation at the time of sacrifice. The magnitude of ear swelling was expressed as percent change in ear thickness using the following formula: ({Delta} in thickness/pre-elicitation thickness) x 100%, where {Delta} in thickness = post-elicitation – pre-elicitation ear thickness. A group of naïve animals received only the elicitation dose of DNFB for the determination of nonspecific ear swelling as a result of application of the hapten in acetone:olive oil. The naive animals exhibited only a 4% change in ear thickness. Left-ear (completely unmanipulated) measurements were also obtained and served as internal controls for each animal.

Following aseptic removal of the spleens, splenocyte proliferation was assessed as described previously [35 ] with minor modifications [18 ]. Briefly, splenocytes were plated in triplicate in 96-well microtiter plates at a density of 200,000 cells per well in RPMI supplemented with L-glutamine (2 mM), penicillin-G (100 U/ml), streptomycin (100 µg/ml), and 10% fetal bovine serum. The viability of the cells was confirmed to be >98% by trypan blue exclusion. Splenocyte cultures were incubated at 37°C in the presence or absence of concanavalin A (Con A; 2 µg/ml) for 72 h. In the absence of Con A, proliferation of splenocytes was minimal in all treatment groups (data not shown). For the final 4 h of culture, the medium was removed and replaced with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT; Sigma Chemical Co.), which in the presence of the mitochondrial enzyme succinate dehydrogenase, is cleaved into a blue-colored product. The optical density of each well was measured using an automatic plate reader at a 540-nm wavelength. Data are presented as mean absorbance for each group.

Determination of circulating levels of IL-6
For measurement of circulating IL-6, blood was obtained by cardiac puncture at the time of sacrifice, and serum was stored at –80°C before assay, as described previously [17 ]. Enzyme-linked immunosorbent assay (ELISA) determined the IL-6 content in serum (Endogen Inc., Cambridge, MA) according to the manufacturer’s specifications. The lower level of detection of the kit was 25 pg/ml.

Hormone replacement
In some studies, aged mice were given estrogen in the form of slow-release polymer pellets, implanted subcutaneously (s.c.; IRA, Tampa, FL), which are designed to deliver a circulating level of ~30 pg/ml (or placebo) as described previously [19 ]. Hormone or placebo pellets were given 7 days before injury.

Statistical analyses
Data are expressed as mean ± SEM unless otherwise noted. In all data shown, N represents the number of individual animals. Differences between groups were determined by ANOVA followed by Newman-Keuls post-hoc test. For mortality studies, the Mann-Whitney U-test was used. A difference of P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Cellular immune responses after injury
As we previously reported, the immunosuppression seen in burn-injured, aged mice was a greater shift in T helper cell type 1 (TH1) to TH2 cytokines than was seen in young-adult mice [36 , 37 ]. Young mice had robust DTH responses 24 h after receiving a 15% TBSA scald or sham injury (Table 1 ). In contrast, DTH was diminished in aged, sham-injured mice (P<0.05) relative to young animals. This level was approximately one-fifth that of young mice. Moreover, the response was nearly absent in aged, burn-injured mice (P<0.01), yielding DTH levels that were about one-third those of aged, sham-injured mice.


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  		Table 1. Cellular Immune Responses after Injury in Young and Aged Mice

 
Comparable with the DTH responses, splenocytes obtained from young-adult mice 24 h after burn or sham injury did not differ in their mitogen-induced proliferative responses (Table 1) . However, splenocytes from sham-injured, aged mice had a significant suppression of Con A-induced proliferation relative to young mice (P<0.01). This was approximately half that of the level observed in sham-injured, young mice (P<0.01). There was no difference in the level of the Con A-mediated, proliferative response of splenocytes from aged, sham- and burn-injured mice.

IL-6 levels in aged, burn-injured mice
IL-6 levels were measured in the serum collected from young and aged mice 24 h after burn or sham injury. The cytokine was undetectable in sham-injured, young mice (Table 2 ). In contrast, after injury, young mice exhibited a significant increase in circulating IL-6 levels in comparison with sham-injured, young mice (P<0.05). The cytokine levels measured in young mice were consistent with our previous studies in which burn injury resulted in a significant elevation in IL-6 levels in young-adult, male B6D2F1 mice [17 ] and female BALB/c mice [38 , 39 ]. These levels are also comparable with the elevated IL-6 levels, which were reported to increase with burn size and correlate positively with rates of mortality and septic or infectious complications [23 , 24 ]. In contrast to young animals, sham-injured, aged mice had elevated, circulating concentrations of IL-6. These levels were similar to that of young, injured mice [18 ]. Moreover, there was a near doubling of the circulating level of the cytokine in aged, injured mice relative to aged, sham mice and young, injured animals (P<0.05).


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  		Table 2. Circulating Levels of IL-6 after Injury

 
Estrogen replacement in aged mice
As physiological levels of estradiol stimulate immune responses, further studies examined the effects of estrogen replacement on cellular immunity after burn injury in aged mice. Placebo hormone replacement did not affect the DTH response in aged mice regardless of injury (Fig. 1 ). Like untreated, aged mice, placebo treatment of aged animals resulted in a marked >75% suppression in the DTH response, relative to placebo-treated, sham-injured aged mice (P<0.05). In contrast to placebo treatment, estrogen supplementation before injury yielded DTH responses in injured mice that were suppressed by only 40%, relative to sham-injured, aged mice (P<0.05). This represents nearly a twofold increase in the response following estrogen treatment.



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  		Figure 1. Estrogen replacement improved the DTH response in burn-injured, aged mice. Seven days before sensitization with the hapten DNFB, aged mice were given s.c. implants containing 21-day slow-release pellets designed to deliver a circulating level of 30 pg/ml 17 ß-estradiol (or placebo hormone) as described in Materials and Methods. Radioimmunoassay confirmed the circulating level of hormone (not shown). Five days after sensitization, mice were subjected to a 15% TBSA scald or sham injury. The DTH response was elicited immediately following injury on the pinna of the right ear and DTH responses measured 24 h later. Data are expressed as percent control relative to aged, sham-injured mice given placebo treatment. In this experiment, the mean % increase in ear thickness in placebo-treated, aged, sham-injured mice was 38.8 ± 7.1; N = 4–6 per group. *, P < 0.05, from all other groups; #, P< 0.05, from sham groups, determined by ANOVA with Newman-Keuls post-hoc analysis.

 
This restoration in cellular immunity in estrogen-treated, aged mice paralleled attenuation in IL-6 production. As shown in Table 3 , there was a marked elevation in the circulating levels of the cytokine in burn-injured, aged mice who received placebo hormone replacement, which was fourfold that of aged, sham-injured mice given placebo (P<0.05). Estrogen replacement failed to significantly alter the circulating levels of IL-6 in sham-injured, aged mice compared with placebo. In contrast, hormone treatment diminished IL-6 production in aged, injured mice. In the presence of estrogen, the level of IL-6 in the circulation was reduced by nearly half to a level that was not significantly above that of sham-injured, aged mice.


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  		Table 3. Estrogen Replacement Attenuates Post-Burn Elevation in IL-6 Levels in Aged Mice

 
To show the extent to which estrogen replacement is therapeutic after injury in aged mice, we examined survival following burn injury (Table 4 ). No mortality was observed in either of the sham groups regardless of hormone status. In contrast, unlike untreated, aged mice, placebo treatment resulted in 58% mortality after injury. Estrogen replacement in burned, aged mice nearly halved that value to 70% survival (30% mortality). This 28% increase in survival in estrogen-treated mice was significant (P<0.05).


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  		Table 4. Effect of Estrogen Replacement on Survival after Injury in Aged Mice

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Aged burn patients have higher rates of mortality after burn trauma than their younger subjects with comparable injuries [1 , 2 , 5 ]. Recently, we used a murine model of thermal injury to show that aged mice succumb more readily after being subjected to a moderate-size burn injury than young-adult mice [36 ]. The mechanisms responsible for the observed differences in mortality in aged subjects have yet to be elucidated. However, evidence suggests that it may be related to the diminished immune status and the production of proinflammatory mediators seen in aged individuals of a variety of species [6 7 8 ].

Our studies confirm earlier findings from our laboratory and others that aged mice exhibit immune dysfunction with suppressed, cell-mediated, immune responses [36 37 38 39 40 ]. The observations are also consistent with the observed temporal difference in the post-burn immunosuppression in male and female mice subjected to identical-size 15% TBSA scald injuries [18 ]. This study by Gregory and co-workers [36 ] showed that the DTH response was intact in young-adult, female, BALB/c mice at 24 h after injury but was suppressed during the second week post-injury. In contrast to the timing of post-burn immunosuppression in female mice, the DTH response in male BALB/c mice occurred early (24 h to 4 days post-injury), after which it recovered [18 , 41 ]. Thus, the early suppression of the DTH response seen after burn injury in aged, female mice is reminiscent of the temporal pattern observed in injured males. However, a larger percentage of the aged mice do not survive their injuries. In another study, Gregory and colleagues [19 ] went on to show that the gender difference in the timing of post-burn immunosuppression was dependent on the gonadal steroid hormone estrogen. Here, we show for the first time that the age-dependent difference in responses to burn injury may involve age-dependent differences in the levels of the gonadal steroid hormone estrogen.

DTH response in aged mice subjected to burn trauma was markedly attenuated relative to other treatment groups. However, there was neither a synergistic nor an additive effect of age and injury on mitogen-mediated splenocyte proliferation, as recently shown in aged mice subjected to hemorrhage [42 ]. The suppressed, proliferative response of splenocytes from aged mice relative to younger animals may be in part a result of the age-associated decrease in the production of lymphocyte-derived cytokines, such as IL-2, described in other systems in uninjured mice [37 , 40 ] and after burn injury [37 ] or hemorrhagic shock [42 ]. The observation that the magnitude of mitogen-induced proliferation is not different in splenocytes from sham- and burn-injured, aged mice, whereas the DTH response does differ between these two groups, may reflect the fundamental differences between the two assays. The DTH response is performed in vivo and is antigen-specific, and Con A-induced splenocyte proliferation is ex vivo and nonspecific.

Evidence from several laboratories reveals that after traumatic injury, functions of multiple immune cell types, including lymphocytes and macrophages, are altered [43 , 44 ]. After burn trauma, for example, T lymphocyte functions, such as proliferation and cytokine production, are depressed [11 12 13 ]. Further investigation shows that diminished, cell-mediated immune responses after burn injury are in part a result of overproduction of macrophage-derived mediators including IL-1, IL-6, TNF-{alpha}, and PGE2 [15 , 17 18 19 20 , 45 , 46 ]. It is interesting that the same set of mediators that are aberrantly produced in patients and animals subjected to traumatic injury are produced in high concentration by monocytes and macrophages from aged individuals in the absence of injury. Many studies have described increased production of these mediators, with a key role for IL-6 in age-induced, immune dysfunction [27 28 29 30 , 47 ]. Low levels of IL-6, for example, are thought to be beneficial to immune function; however, higher concentrations are clearly immunosuppressive [17 , 18 , 22 ] and correlate with a poor prognosis in trauma patients [21 , 24 , 48 ]. Furthermore, young-adult burn patients who do not survive following burn trauma have circulating IL-6 levels that are almost tenfold higher than in surviving patients [21 , 23 ]. Thus, the aberrant production of proinflammatory mediators in healthy, aged subjects may contribute to the increased immunosuppression and subsequent mortality seen after relatively minor injuries.

The present study confirms our earlier findings that circulating levels of IL-6 are significantly elevated in aged, injured mice relative to aged, sham and young, injured animals [36 ]. This observation, taken along with earlier work showing that marked elevation in circulating levels of this cytokine correlates with post-injury immunosuppression [17 , 18 , 49 , 50 ], suggest that therapies designed to block IL-6, including treatment with anti-IL-6 antibodies, may be therapeutic in aged, burn-injured mice as it was in young-adult mice subjected to traumatic injury [18 , 49 , 51 , 52 ]. Preliminary data from our laboratory suggest that the administration of anti-IL-6 antibody to burn-injured, aged mice partially restores the DTH response, and it completely restores splenocyte proliferation (Kristy A. Grabowski, Lisa A. Duffner, E. J. Kovacs, unpublished observation). This suggests that although IL-6 is an important mediator of post-trauma immunity, other factors are likely to work in parallel or in series with this cytokine.

It is not clear which cell type(s) is (are) responsible for the differences in the circulating levels of IL-6 seen in young and aged mice regardless of injury. A good deal of evidence suggests that macrophages are capable of producing high levels of this cytokine (for a review, see ref. [50 ]). However, we and others have shown that in the absence of injury, peritoneal macrophages isolated from aged mice and stimulated with lipopolysaccharides in vitro produce less, rather than more, IL-6 than comparably treated cells obtained from young mice [53 , 54 ]. Moreover, the same pattern of cytokine production resulted from the culture of splenic macrophages from young and aged mice (ref. [53 ] and Eric D. Boehmer, E. J. Kovacs, unpublished observation), suggesting that thioglycolate elicitation was not critical to the age-dependent difference in cytokine production. Hence, the source of the elevated basal levels of IL-6 in aged mice may be a cell type other than the macrophage, such as leukocytes, fibroblasts, or endothelial cells, all of which are capable of producing the cytokine [50 ].

Regardless, additional evidence reveals that treatment of aged mice with low proestrus levels of estrogen partially restores the DTH response and attenuates IL-6 production. These observations are consistent with our previous studies in severely immunosuppressed male mice given ethanol before burn injury [55 ]. In these studies, administration of estrogen after injury attenuated IL-6 production, boosted DTH and splenocyte-proliferative responses, and improved survival after a bacterial infection. The mechanism responsible for the estrogen attenuation of IL-6 production has yet to be confirmed, but evidence from our laboratory and others suggests that it involves nuclear factor-{kappa}B [55 56 57 ].

The observed decrease in circulating IL-6 after estrogen treatment is consistent with the clinical studies in which administration of estrogen to menopausal women lowered circulating levels of IL-6 without affecting other cytokines [34 ]. Moreover, other reports focused on improvement in immune parameters, including T cell proliferation, in post-menopausal women given estrogen-containing hormone replacement [32 , 33 ].

Finally, we were pleased but somewhat surprised to see the marked improvement in survival after burn injury of aged mice given estrogen replacement at a concentration designed to deliver proestrus levels of the hormone. This improvement in immunity and survival is likely to involve more than attenuation of aberrant IL-6 production, as estrogen has been shown to alter the production of a handful of proinflammatory mediators, including IL-1, IL-6, TNF-{alpha}, and PGE2 [58 59 60 61 62 ]. Regardless of the mechanism, we feel that using this "real world" test clearly shows the benefit of this novel therapy for burn injury. Current studies are underway to determine if treatment of aged mice with estrogen after injury has comparable, beneficial results.

In summary, these studies reveal that mortality is higher in aged mice subjected to traumatic injury relative to young mice and can be partially reversed by estrogen replacement. Cell-mediated, immune responses are impaired in aged, burn-injured mice relative to other treatment groups, and aged, burn-injured mice have higher circulating levels of IL-6. These parameters, too, can be partially restored after estrogen treatment. Further studies are needed to elucidate mechanisms responsible for the therapeutic efficacy of estrogen treatment after injury to determine if it should be administered to burn-injured patients of all ages.


   ACKNOWLEDGEMENTS
 
NIH AG18859 (E. J. K.) and AG00997 (P. L. W.) supported this work. The authors extend a special thanks to members of the Immunology and Aging Program at Loyola University Medical Center, especially Dr. Douglas E. Faunce and Mr. Eric D. Boehmer, who provided critical review of the manuscript. Lisa A. Duffer provided technical assistance for these studies.


   FOOTNOTES
 
2 Present address: Chicago College of Osteopathic Medicine, Midwestern University, 555 31st Street, Downers’ Grove, IL 60515. Back

Received November 5, 2003; revised December 23, 2003; accepted January 9, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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